Process for the production of cyclic lactones



Patented Sept. 14, 1948 PROCESSFFOR THE PRODUQ'lI-IONeQ-F- CYCLIC "LACTQNEST,

Haydn Geoffrey: Dickenson,

Warri'ngton, England, assignor; to Ward, Blenkinsop & Company Limited, London, England-a British'com- NoDrawing; Application February 8, 1947, Serial In Great Britain February 7 Section 1, Public Law 6903Augusta8, 1946 5 Claims. 1" .Ifhispinyrantion relates to the production of cyclic lactonesr' of the .coumarinseries;

Hitherto, cyclic-lactones of the coumari-rr series hayebeen obtained by condensing o-acetoxybene zoyl, chlorideand itshomologues: with sodiomalonicester (-Anschiitz et al., Annalen, volume-3fi7rpage 1,74) and, decarboxyla-ting the produets; by, treatment with,alkali. There are difilculties, in carrying, out this process however and; the yieldssarernot, in general, very good.

liieretofmtezlittler usel has .been made of. dialkyl carbonates v as reactants in the Claisen, reaction. Wislicenus; Berichte derDeut. Chem, Gast, VOl-r ume20, page-2930i (-1.877 failed, to condense ethyl carbonate-with ethyl acetate. Subsequently Lux, ibid, volume 62, page 1824 (1929), obtained an 18%, yieldofdiethyl; malonate by adding ethyl acetate-toe refluxing mixturelof benzene,;diethyl,

carbonate andpowdered sodium. More recently" Wallinfordget al.,, J, Am; Chem.- Soc.,;,volume 3,-, page-2056 (1941'), have'shown that-this type of reaction is. reversible iandi that the yield can be increased, if one-ofthe; reaction; products" is progressively removed from the reaction zone. In a. subsequent paper these authors; ibid, page 2252, have examined the reaction between diethyl, car:- bonatew and as series; of" ketones in, the: presence of alkali metal alcoholates. Acetophenone and several p-substituted' acetophenones" have been shown tov give, varying yields of the corresponding benzoyl acetates whilst the homologous acylo phenones have been shown to give the corresponding a-benzoyl" esters; In ordento obtain a maximum yield of the l desired' product theseauthorstookisteps to remove theliberated alcohol from the reaction mixture as i-twas formed;

litazhasz nowabeen found that the'Claise-n reaction between a carbonic ester and an o-hydroxy acylophenone can be utilized for the production of cyclic lactones of the coumarin series in good yield.

, According to the present invention a process for the production of a derivative of a cyclic lactone of the coumarin series comprises condensing a dialkyl or ,diaralkyl carbonate with an o-hydroxy acylophenone of the general formula OH in which R is an alkyl group in the presence of an alkali metal alcoholate. In order to liberate the free cyclic lactone therefrom the resulting derivative is treated with acid.

According to a feature of the invention an excess, of, dialkylor diaralkyl carbonate, based on the orthohydroxy aryl-ketone; is employed;

Accordingto a funtherfeature of the invention the alkali, metal alcoholateemployed is a sodium, orpotassi-um alcoholate Whilst anyv dialkyl or' diaralkyl carbonate may. beemployed itzis generally preferred. to employ diethyl. carbonate.

It is' considered. that, the-reaction which. takes, place between the carbonic ester and-the :ketoneof the said general formula involves theintere mediate production in situ of an a-(ortho-hydroxybenzoyl) acyl ester-ora derivative thereof which; then undergoes: cyclization to {produce-the corresponding:coumarin derivative under the re-- action conditions:

derivative, substantially as it is formed. The initial Claisen condensation is then no longer readily reversible: It is still desirable, although not essential; to remove. the liberated" alcohol since removal thereof; prevents the lactone ring re opening as well as minimizing-hydrolysis ofther carbonic'=,ester and according-to a further feature oiithe' invention the condensation is carried. out

by heating the reactantsina solvent which isiin ert with. respect thereto J and" which forms a low boiling azeotropewith the'alcohol liberated dur ingthe reaction.

'li'lie ketone or ester which: constitutes astarting material in the process hasahydroxygroup pres entzin the ortho positiorr in thebenzene ring;

Othervsubstituentssuch as alkyl groups-may also bepresentim thebenzene ring'so long as: these may be ortho-hydroxyacetophenone= or an homologue thereofi such: as an: ortho-hydroxy propioor butyrophenone. When these reactants are employed under Claisen condensation conditions and the products are treated with aqueous acid, lactones are obtained which, in one tautomeric form may be described as 4-hydroxycoumarins.

The reaction may be carried out by heating the carbonic ester and the o-hydroxyacylophenone with an alkli metal alcoholate, with or without a substantially anhydrous non-alcoholic solvent such as benzene, toluene or xylene. The alcoholate may first be produced in the reaction vessel from the corresponding metal, for example, sodium or potassium, and the alcohol, for example, ethyl, a propyl or a butyl alcohol, the excess alcohol removed and the reactants, with Thus-under Claisen reactionw" conditionsthe esterprodu'ctnappearsrto undergot further reaction, presumably forming a cyclizeds 3 or without non-alcoholic solvent, added to the reaction vessel.- The'reactionmixture is preferably heated. The product may be separated by adding water, separating the non-aqueous Example 1 1.7 parts of sodium metal were dissolved in 25 parts of dry ethyl alcohol and when completely dissolved, the excess alcohol removed by distillation, finally under reduced pressure,

To the dry sodium ethoxide thus produced was added 25 parts of diethyl carbonate followed by 5 parts of o-hydroxyacetophenone, th mixture being constantly stirred. The semi-solid mass was heated'on the water-bath for 4 hours and then dissolved in '75 parts of water. The upper layer of unchanged diethyl'carbonate was separated, and the aqueous layer acidified with hydrochloric acid using Congo Red as indicator. The precipitatedihydroxy-coumarin was removed by filtration and purified by crystallisation from water or dilute alcohol. M. Pt. 209 10.

Example 2 The condensation of Example 1 was repeated using instead of o-hydroxy acetophenone, a corresponding m-olar amount of o-hydroxy propiophenone. The product was 3-methyl-4-hydroxycoumarin. M, Pt. 226-8 C.

Example 3 1.7 parts of sodium metal was dissolved in 25 parts of dry ethanol and the solution evaporated to dryness in vacuo. To the dry sodium ethylate so obtained was added 35 parts of dry benzene, 5 parts of o-hydroxyacetophenone and 7 parts of diethyl carbonate. The mixture was then heated under a short'fractionating column so that the azeotrope of benzene with the ethyl alcohol formed in the condensation distilled from thereaction mixture. When 20 parts of benzene had been collected, a further 35 parts of dry benzene was added to the distilling reaction mixture and distillation resumed. After a total of four hours heating the residual benzene was removed under reduced pressure and the reaction mass worked up as in Example 1. 4-hydroxycoumarin was isolated as before. M. Pt, 209-l0 C.

What I claim is:

1. A process for the production of a coumarin which comprises treating an ortho-hydroxy acylophenone, having the general formula OH in which R is a lower alkyl group with a carbonate having the general formula CO.(OR )2 in which R is selected from alkyl and aralkyl groups in the presence of an alkali metal alcoholate and treating the product with acid to liberate said coumarin. v

2. A process for the production of a coumarin which comprises heating an ortho-hydroxy a'cylophenone, having the general formula in which R. is a lower alkyl group with a lower dialkyl carbonate in the presence of an alkali metal alcoholate and treating the product mineral acid to liberate said coumarin.

solvent which forms a low boiling azeotrope with ethyl alcohol, in the presence of an alkali metal alcoholate, distilling from the reaction mixture the azeotrope produced and treating the product with mineral acid to liberate said coumarin.

4. A process for the production of 3-methyl-4- hydroxycoumarin which comprises heating ortho-' hydroxypropiophenone with diethyl carbonate in the presence of an alkali metal alcoholate' and treating the product with mineral acid to liberate said coumarin. r

5. A process for the production of 4-hydrox'ycoumarin which comprises heating ortho-hydroxyacetophenone with an excess of diethyl car bonate and a solvent which forms a low-boiling azeotrope with ethyl alcohol in the presence of an alkali metal alcoholate, distilling from the reaction mixture the azeotrope produced, removing the remainder of said solvent and treating the residue with mineral acid to liberate said coumarin.

HAYDN GEOFFREY DICKENSON.

REFERENCES CITED The following references are of record in the file of this patent:

Wallingford et al., J. Am. Chem. Soc, 63, 2252 (1941) (Copy in Sci. Lib.)

Gilman, Organic Chem., vol I, pages IMO-i041,

2nd ed., J. Wiley & Sons.

Smith et al., J. of Organic 

